This invention relates to the process for the production of enantiomerically pure or optically enriched sertraline-tetralone from a mixture containing two enantioners using continous chromatography or single column high performance chromatography. Some examples of continuous chromatography are liquid chromatography technologies know by the names cyclojet, and simulated moving bed chromatography (SMB). The concept of SMB was described in the late 1950""s (U.S. Pat. Nos. 2,957,927 and 2,985,589) and has long been used in the petrochemical and sugar industries, Nicoud, R. M., LC-GC Intl. 5 (5), 43 (1992). Further reference can be made to U.S. Pat. Nos. 3,205,166; 3,291,726; and 3,310,486. A high efficiency continuous separation process using SMB is disclosed in U.S. Pat. Nos. 4,402,832; 5,518,625; 5,434,298: 5,434,299; 5,498,752; and Re 35,919 which are all incorporated by reference. In addition, xe2x80x9cChiral Discrimination on Polysacchride Derivativesxe2x80x9d, Yashima and Okamoto, Bull. Chem. Soc. Jpn., 68, 3289-3307(1995) discusses separation characteristics useful in chiral chromatography phases. Further discussion by Okamoto et. al. are included in The Journal of Chromatography, Part A, Volume 694, pp 101-109 (1995).
Sertraline-tetralone is the starting raw material In the synthesis of Zoloft (sertraline hydrochloride), a drug currently marketed for the treatment of depression as disclosed in U.S. Pat. Nos. 4,536,518; 5,196,607; 5,442,116; and 4,777,288, all incorporated by reference. Current processes for preparing this compound as described in the above patents resolve the racemic mixture at a late stage. This late stage resolution requires the undesired enantiomer to be carried through several steps. A significant benefit is obtained if an enantiomerically pure sertaline-tetralone is used as the starting material.
SMB combines the high resolution power of high performance liquid chromatography (HPLC) with the lower costs of classical separation processes such as crystallization. The costs of the SMB process can be reduced even further, if it is combined with a racemizatlon step converting the Inactive enantiomer Into the racemic form which could then be recycled back Into the process.
A process for chromatographically resolving an enantiomerically pure or optically enriched sertraline-tetralone from a mixture containing two enantiomers uses continuous chromatography or single column high performance chromatography. The continuous chromatography comprses a liquid mobile phase comprising at least one polar solvent and a solid chiral stationary phase comprising a derivatized polysaccharide that is selected from the amylosic, cellulosic, chitosan, xylan, curdlan, dextran and inulan class of polysaccharides. Some examples of the continuous chromatography methods are the cyclojet process or simulated moving bed chromatography process. The simulated moving bed chromatography process is preferred. The process uses a chiral stationary phase which is a member of the amylosic or cellulosic class of polysaccharides selected from cellulose tribenzoate, cellulose tricinnamate, amylose tricinnamate, amylose tris[(S)xcex1-methyl benzyl carbamate], amylose 3,4-substituted phenyl carbamate and amylose 4-substituted phenyl-carbamate. Preferably the chiral stationary phase is an analog of amylose (3,4-substituent phenyl carbamate) wherein the subsfituent is selected from 3-chloro-4-methyl, 3-methyl-4-chloro or 3-fluoro-4-methyl. The chiral stationary phase can also preferably be a cellulose tricinnamate polysaccharide analog. The mobile phase comprises a solvent that is selected from heptane, hexane, isopropyl, ethanol, methanol. methyl acetate, acetonitrile, methyleno chloride, ethyl acetate and/or mixtures thereof. Preferably the mobile phase is selected from acetonitrile and/or a mixture of acetonitrile and methanol or ethanol and/or a mixture of ethanol and ethyl acetate. In one embodiment the chiral stationary phase is cellulose tricinnamate with a mobile phase of ethanol/ethyl acetate wherein the percentage of ethanol in the mobile phase mixture is greater than 50%. Preferably the chiral stationary phase is amylose (3-chloro-4-methylphenyl carbamate) and the mobile phase is acetonitrile/methanol wherein the percentage of acetonitrile in the mobile phase mixture is greater than 50%. The chromatographic retention times are increased or decreased by varying the mobile phase components. The separation affords at least one of the enantiomers a recovery of greater than or equal to 90 percent. The temperature range is about 5 to 45xc2x0 C., preferably 20 to 40xc2x0 C. The separation factor xcex1 is about 1.2 to 5.0. Using a temperature of about 40xc2x0 C. takes advantage of an increased solubility of sertratine tetralone in the mobile phase. The chiral stationary phase polysaccharide derivative can also be immobilized on silica gel, zirconium, alumina, ceramics and other silicas.